Pancreatic cancer is a devastating disease that is refractory to standard chemotherapies, as demonstrated by the low five-year survival rate of 8%. The objective of this proposal is to assess a novel, highly promising therapeutic for the treatment of pancreatic cancer, employing comprehensive in vitro and preclinical in vivo testing prior to clinical evaluation studies. The sigma-2 (S2) receptor is overexpressed in pancreatic cancer, and small molecule ligands to this receptor localize to these tumors. In addition, PDAC cancer cells rapidly internalize selected sigma-2 ligands. This finding prompted us to explore the possibility of using these ligands to deliver additional therapeutic payloads to PDAC tumor cells via chemical linkage with our ligands. We have successfully used S2 ligands to deliver structurally diverse compounds including both peptides and small molecule therapeutics (classic chemotherapeutics [rapamycin] and peptidomimetics), into the cancer cells both in vitro and in vivo. In each case, the activity profiles of the conjugates were far greater than the isolated components or their equimolar combinations. Based on this delivery concept, we combined the tumor selectivity of the S2 ligand SV119 with a promising drug cargo that induces cell death selectively in PDAC (dm-Erastin), by creating a single small molecule conjugate (SW V-49). We have shown that this conjugate efficiently kills tumor cells in stroma-rich pancreatic cancer models with only limited signs of systemic toxicity. The key tasks of this project involve pharmacology and toxicity drug testing employing PDAC cell lines in vitro (murine and human), primary patient-derived 3D organoid in vitro cultures as well as syngeneic (mouse) and patient-derived xenograft models (PDX) of pancreatic cancer.